Studies of childhood acute lymphoblastic leukemia (ALL) focus on the investigation of the clinical pharmacology of antileukemic drugs to identify more rational approaches to their use, the development of new antileukemic agents, and the development of more effective and less toxic approaches for the treatment and prevention of CNS leukemia. We are conducting a pilot trial evaluating the role of thioguanine (in place of the standard thiopurine, mercaptopurine) in patients with lower risk ALL based on our preclinical studies demonstrating that thioguanine is more potent and less schedule-dependent than mercaptopurine in leukemic cell lines and lymphoblasts from children with ALL and on our phase I trial of thioguanine administered as a continuous intravenous infusion. The pilot leukemia trial incorporates a number of pharmacokinetic/pharmacodynamic endpoints including the plasma and CSF pharmacokinetics of thioguanine after oral and intravenous administration and measurement of RBC thioguanine nucleotide levels. Our pharmacokinetic studies of thioguanine have demonstrated a capacity-limited, elimination mechanism and a pharmacokinetic model was developed to describe the disposition of thioguanine. In addition, we identified a new circulating metabolite of thioguanine (8-oxo-thioguanine). The pharmacokinetics of antileukemic agents administered by continuous infusion is being evaluated in high-risk patients and correlated with toxicity of therapy and disease outcome. A prospective study of the bioavailability of oral mercaptopurine (MP) and methotrexate (MTX) maintenance therapy in a large cohort of low and average patients revealed considerable inter- and intra-patient variability of plasma drug concentrations with both agents (MP > MTX), a poor correlation between dose and plasma drug exposure, and no relationship between plasma drug levels and disease outcome. New agents under development that may be useful in the treatment of acute leukemias include the retinoids (all-trans- and 9-cis-retinoic acid), tomudex, paclitaxel and docetaxel, and the new methotrexate rescue agent carboxypeptidase-G2. Our clinical trials have identified alternative CNS preventive regimens in which the combination of intrathecal and high-dose systemic therapy were demonstrated to be as efficacious and less neurotoxic than the standard regimen of cranial radiation and intrathecal methotrexate. We are also developing a number of new intrathecal agents (diaziquone, mercaptopurine, mafosfamide, topotecan) which have proven useful in the treatment of overt meningeal leukemia. There was no HIV/AIDS-related work in this project.